The invention relates to methods for treating disorders responsive to DHFR inhibition including neoplastic diseases, rheumatoid arthritis, restenosis, multiple sclerosis, lupus, infections, and ectopic pregnancy. The inventive method comprises administering to a patient in need of treatment a therapeutically-effective amount of a composition comprising certain aromatic, primarily non-aliphatic, molecules that may be found in coal tar.
Coal tar formulations have been investigated for use in treatment of a variety of mammalian health disorders. For example, a non-aliphatic pyrimidine composition known as Liquor Carbonis Detergens (LCD), a by-product of coal tar distillation, has been established as effective in treating certain skin disorders, particularly psoriasis. See, e.g., U.S. Pat. No. 4,102,995 to Hebborn, xe2x80x9cTar Gel Formulation.xe2x80x9d Coal tar contains a number of aromatic compounds, e.g., representative constituents of LCD may include benzene, toluene, xylene, phenol, indene, creosol, chrysene, napthalene, methylnapthalenes, thianapthalene, quinolines, acenaphthene, dibenzofuran, fluorene, phenanthrene, anthracene, carbazole, fluoranthene, pyrene, and benzo(a)anthracene.
The inventor herein has extensively studied coal tar formulations, their constituents, and their use in the treatment of human conditions and disorders. U.S. Pat. Nos. 5,512,275 and 5,609,858 (which are incorporated herein by reference), issued to the present inventor and relate to the treatment of androgenic alopecia with use of LCD. U.S. application Ser. No. 08/953,362 filed by the present inventor on Oct. 17, 1997, xe2x80x9cCoal Tar Formulations for the Inhibition of NADPH Synthesis for Therapeutic Applicationsxe2x80x9d (hereinafter referred to as the ""362 application), relates to use of LCD formulations in the treatment of cancer.
Rheumatoid arthritis is an autoimmune disease which causes chronic inflammation of the joints, the tissue around the joints, and other organs in the body. Autoimmune diseases occur when the body tissues are mistakenly attacked by its own immune system. The immune system is a complex organization of cells and antibodies designed normally to xe2x80x9cseek and destroyxe2x80x9d invaders of the body, particularly infections. Patients with these diseases have antibodies in their blood which target their own body tissues, where they can be associated with inflammation.
The joint inflammation of rheumatoid arthritis causes swelling, pain, stiffness, and redness in the joints. The inflammation of rheumatoid disease can also occur in tissues around the joints, such as the tendons, ligaments, and muscles. In some patients with rheumatoid arthritis, chronic inflammation leads to the destruction and deformity of the joints. When the disease is active, symptoms can include fatigue, lack of appetite, low grade fever, muscle and joint aches, and stiffness. During flares, joints become red, swollen, painful, and tender. This occurs because the lining tissue of the joint (synovium) becomes inflamed, resulting in the production of excessive joint fluid (synovial fluid). The synovium also thickens with inflammation (synovitis).
Two classes of medications are used in treating rheumatoid arthritis: fast-acting xe2x80x9cfirst-line drugs,xe2x80x9d and slow-acting xe2x80x9csecond-line drugs.xe2x80x9d The first-line drugs, such as aspirin and cortisone (corticosteroids), are used to reduce pain and inflammation. Slow-acting second-line drugs include gold, methotrexate and hydroxychloroquine (PLAQUENIL), which is related to quinine. DHFR inhibition is the mechanism of action of the antifolate drug methotrexate (MTX) and it would be advantageous to provide alternatives to MTX in treating arthritis and other diseases due to its long-term toxicity which is known for shortening life-span expectancy.
The instant invention is based on applicant""s discovery that formulations based on coal-tar and LCD constituents are useful in treating disorders responsive to DHFR inhibition, including rheumatoid arthritis, restenosis, multiple sclerosis, lupus, infections, ectopic pregnancy, and neoplastic diseases. Thus, summarily described, the invention comprises a method for treating disorders responsive to DHFR inhibition comprising administering to a patient an effective amount of a composition comprising a plurality of aromatic compounds found in coal tar and in particular, a plurality of compounds selected from the group consisting of acenapththene, methylnaphthalene, anthracene, benzo(a)anthracene, biphenyl, carbazole, chrysene, dibenzofuran, fluoranthene, fluorene, indene, napththalene, phenanthrene, pyrene and quinoline.
Applicant incorporates by reference the entire contents of her ""362 application, referenced above. It is known that dihydrofolate reductase (DHFR) catalyzes the NADPH-dependent reduction of 7,8-dihydrofolate (H2F) to 5,6,7,8-tetrahydrofolate (H4F) and is necessary for maintaining intracellular levels of H4F, an essential cofactor in the synthetic pathway of purines, thymidylate and several amino acids. DHFR inhibition is the mechanism of action of MTX and trimethoprin which are used to treat a wide range of diseases including many cancers, infections, rheumatoid arthritis, multiple sclerosis, and lupus. Applicant has discovered that compositions based on coal tar constituents are also useful in inhibiting DHFR production and thus, for treating diseases responsive to such inhibition.
It is believed the inventive compositions inhibit the transfer of the hydrogen ion to dihydrofolate reductase, thus preventing metabolism within the nucleus of tetrahydrofolate, which is required to carry one-carbon groups in the synthesis of purine nucleotidase and thymidylate. Neoplastic cells are more responsive than slower dividing normal cells to this resulting interference with DNA synthesis, repair, and cellular replication. The invention functionally replicates MTX. The method of DHFR inhibition, however, is believed to be a non-competitive binding, electron transport, or allosteric affect on NADPH, the cofactor reducing agent, rather than by competitive blocking.
The instant compositions may be used as an alternative to methotrexate. Methotrexate is an anti-inflammatory, antiallergic, and immunosuppresive medication. Methotrexate is indicated in managing selected adults with severe, active, classical or definite rheumatoid arthritis who have experienced adverse effects or insufficiently therapeutic responses from a trial of first-line therapy including full dose NSAIDs and usually a trial of at least one or more disease-modifying antirheumatic drugs. Methotrexate has gained popularity among physicians as an initial second-line drug for treating arthritis because of its effectiveness and relatively infrequent side effects. However, like other immunosuppresive medications, it can present risks, e.g., a depressed bone marrow function and anemia, a low white cell count, and low platelets counts. A low white count can increase the risk of infections, and a low platelet count can increase the risk of bleeding. Methotrexate also is effective in treating other disorders, e.g., it has been used to induce miscarriage in patients with ectopic pregnancy. It has been shown to be effective for systemic lupus erythematosus, especially in patients who are not improving with steroid therapy. Methotrexate has shown effectiveness in providing relief in patients with lupus and various forms of arthritis.
The invention may be used as an alternative to MTX in treating the above-referenced disorders and several types of cancer. Inventive compositions may be used as a single agent to treat cancers of the prostate, melanoma, lung, particularly squamous cell and small cell types, meningeal leukemia, gestational choriocarcinoma, chorioadenoma destruens, and hydatidiform mole. Other possible cancers include: breast, colon, bone, testicular, epidermoid cancers of the head and neck, advanced mycosis fungoides, and advanced stage non-Hodgkin""s lymphomas.
One preferred composition for use in the inventive method is referred to herein as xe2x80x9cOncoX.xe2x80x9d OncoX may be prepared through distillation of coal tar or it may be synthetically prepared as including the constituents of a coal tar formulation. The composition may be combined either by coal tar distillation or mixed from pure chemicals in a solution of DMSO which serves as a solvent. One advantageous formulation (percentage by weight) is set forth below:
The percentage weight may vary slightly if produced by distillation. This formulation may additionally have at least one of anthracene (9.1%) and benzo(a)anthracene (1%). The resultant mixture may be diluted in DMSO to the equivalent of 0.0014 mg/Mol. for use parenterally, intramuscularly, by injection to the spinal column, or converted to ingestible (pill) form. The formulation can also be diluted in ethanol and other alcohol carriers and delivered to the skin, bloodstream and intramuscularly as well as through the spinal column with alternative acceptable carriers. A preferred range of constituents for the formulation in weight percentages consists essentially of 0.4 to 0.6% acenapththene, 0.1 to 0.7% 1-methylnaphthalene, 0.8 to 1.4% 2-methylnaphthalene, 7.45 to 9.1% anthracene, 0.7 to 1.0% benzo(a)anthracene, 6.0 to 10% biphenyl, 3 to 5% carbazole, 0.2 to 0.9% chrysene, 3 to 5% dibenzofuran, 9 to 12% fluoranthene, 5 to 8% fluorene, 0.4 to 0.5% indene, 4 to 6% napththalene, 20 to 30% phenanthrene, 6 to 9% pyrene and 0.3 to 0.4% quinoline.
OncoX is a solution containing 5% of a coal tar formulation. The formulation is dissolved in a 15% DMSO/85% IPA solution. A preferred dose is 0.0114 milligrams/Mol. of solution, equivalent in potency to 23 micrograms of methotrexate, but may vary based on the condition treated and the severity of the disease. The invention may also be incorporated into lipid carriers for administration and targeted delivery to desired portions of the body. A formulation for OncoX is set forth below:
OncoX constituents
Formulations for Delivery
The inventive compositions may be systemically administered via injection, typically by intravenous injection. Other injection routes, such as subcutaneous, intramuscular, or intraperitoneal, can also be used. Alternative means for systemic administration may include transmucosal and transdermal administration using penetrants such as bile salts, fusidic acids or other detergents. In treating multiple sclerosis, rheumatoid arthritis, metastatic cancer, lupus and ectopic pregnancy, the compositions may be delivered by injection or IV. The use of monoclonal antibodies is anticipated. In treating certain disorders, such as karposi sarcoma, administration generally may be topical or localized, in the form of salves, pastes, gels and the like.
If properly formulated in enteric or encapsulated formulations, oral administration may also be used. An additional method of administration is by dilution with acetic acid and DMSO (solvents) and a buffer solution and saline carriers at a dosage which will permit sufficient molecular release of the cytotoxins to provide a lengthy half-life. In this case, the anticipated high level of protein serum binding is used to advantage, acting as a dose-limiting and time-release method, much like many NSAID""s.